Thrombosis is a pathological process in which platelets aggregation or a fibrin clot occludes a blood vessel. Anticoagulants interfere with fibrin formation and are used for prophylaxis of thrombosis.
The blood coagulation system involves a number of zymogens (inactive enzymes) that are activated through a cascade of enzymatic reactions. The final step in coagulation is the formation of the fibrin clot from fibrinogen by a trypsin-like serine protease thrombin, which in turn is generated from prothrombin by the action of factor Xa. Accordingly, the blood coagulation enzyme thrombin plays a central role in hemostasis and thrombosis. Thrombin inhibitors are therefore expected to be effective anticoagulants by inhibition of platelets, fibrin formation and fibrin stabilization. It also activates factor V and factor VIII in a positive feed back reaction.
In recent years, numerous thrombin inhibitors have been developed as potential antithrombotic and anticoagulant agents, for example, tripeptide derivatives such as PPACK [D-Phe-Pro-Arg-CH.sub.2 Cl, Thromb. Res., 14, 969 (1979)], D-Phe-Pro-Arg, Boc-D-Phe-Pro-Arg, and D-MePhe-Pro-Arg [J. Med. Chem., 33, 1729 (1990)], DuP-714 [Ac-(D)-Phe-Pro-boroArg-OH, J. Biol. Chem., 265, 18289 (1990)], Efegatran [D-MePhe-Pro-Arg.H.sub.2 SO.sub.4, Thromb. Haemost., 67, 325 (1992)], Inogatran [HOOC--CH.sub.2 --(R)Cha-Pic-Nag, where Cha: cyclohexylamine, Pic: pipecolic acid and Nag: noragmatine, WO 93/11152, Blood Coag. Fibrinol., 7, 69 (1996)] and CVS-1123 [(CH.sub.3 CH.sub.2 CH.sub.2).sub.2 --CHCO--Asp(OCH.sub.3)-Pro-Arg, WO 93/15756] and piperidine amide derivatives such as Argatroban [U.S. Pat. No. 4,258,192, Thromb. Haemost., 18, 13 (1992)] and NAPAP [J. Biol. Chem., 266, 20085 (1991)]. But, they are not necessarily sufficient for practical use in view of oral bioavailability, inhibition selectivity for thrombin over other serine proteases, stability, duration of action and toxicity at the therapeutic dosages.
In view of the above, the present inventors have conducted intensive studies to develop potent thrombin inhibitors which are orally bioavailable, selective in inhibition of thrombin over other serine proteases and sufficient for practical use. As a result of such efforts, we have found that the compound of formula (I) exhibits excellent thrombin inhibitory activity even when orally administered and has a high selectivity for thrombin in comparison to trypsin, and have thereby completed the present invention.